Combined small-cell lung cancer (cSCLC) is a rare condition in which tumors contain characteristics of both small-cell and non-small-cell lung cancer. Recent research reveals that the tumors do not contain separate cancers, but rather the cells progress and transition between multiple cancer types, making the tumors more aggressive and more difficult to treat. The findings are detailed in the paper, “Spatial Multi-Omics Unveils the Monoclonal Origin, Neuroendocrine Plasticity and Microenvironment Niches in Combined Small-Cell Lung Cancer,” published in Cell Reports Medicine.
Co-led by the Institute for Systems Biolodgy (ISB), the study employed spatial and single-cell genomic strategies to examine the tumors. Researchers discovered that the tumors’ cells begin as a single familial cancer cell and transform identities.
“We found that these tumors are not simply mixtures of different cancer types,” said Wei Wei, PhD, in a news release. Dr. Wei is co-corresponding author of the study and associate professor at ISB. “They are dynamic systems, with cancer cells actively changing their identity. That flexibility may help explain why they are so difficult to treat.”
The study further revealed how tumors subsist in intermediate or hybrid states, allowing them to carry features of two or more cancer cell types simultaneously. Of the SCLC-like tumors the researchers analyzed, approximately one-third demonstrated mixed identities. The authors said this suggests that cancer progression is a continuum.
“By combining spatial genomics, single-cell analysis and multiregion sequencing, we were able to trace how these tumors evolve across both space and time,” said Fudan University’s Qihui Shi, PhD, the study’s other co-corresponding author. “This approach allowed us to capture transitional cell states that are not visible using conventional methods.”
The researchers created a cSCLC detector — a four-gene diagnostic tool that could help identify mixed tumors with more accuracy. They developed the tool based on the study’s primary finding that small-cell and non-small-cell segments derive from the same familial tumor and share early trunk mutations even though they look different under a microscope.
The team used the cSCLC detector to analyze data from patients with diagnosed small-cell lung cancer. The tool identified a significantly higher percentage of cases with mixed tumors, which suggests the rare condition may be underdiagnosed.
The study results indicate the importance of how cancer cells change identity and interact with the environment, the authors said.
“Cancer is not static,” Dr. Wei said. “To treat it effectively, we need to understand how it evolves — not just what it is at a single point in time.”
